Shedding; Towards a New Paradigm of Syndecan Function in Cancer

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Shedding; towards a new paradigm of syndecan function in cancer

Sojoong Choi, Hawon Lee, Jung Ran Choi & Eok Soo Oh* Department of Life Sciences, Division of Life and Pharmaceutical Sciences, Center for Cell Signaling and Drug Discovery Research, Ewha Womans University, Seoul 120-725, Korea

Syndecans, cell surface heparansulfate proteoglycans, have (ectodomain) is required for the release of EGF and the regu- been proposed to act as cell surface receptors and/or corecep- lation of diverse functions, including development, growth, tors to play critical roles in multiple cellular functions. Howev- and differentiation (1). The ectodomain shedding of mem- er, recent reports suggest that the function of syndecans can be brane-tethered EGFR ligands are mediated by protease TACE/ further extended through shedding, a cleavage of extracellular ADAM17 (2) and ADAM12 (3). During osteoclastogenesis, re- domain. Shedding constitutes an additional level for control- ceptor activator of NF-κΒ ligand (RANKL) is cleaved proteolyti- ling the function of syndecans, providing a means to attenuate cally and released from the cell surface by tumor necrosis fac- and/or regulate amplitude and duration of syndecan signals by tor-α (TNF-α)-converting enzyme (4). Extracellular domain modulating the activity of syndecans as cell surface receptors. shedding is also a characteristic of other growth factors, such Whether these remaining cleavage products are still capable of as transforming growth factor-α (TGF-α) and TNF-α as well as functioning as cell surface receptors to efficiently transduce cell adhesion molecules, including L-selectin (5) and E-cadher- signals inside of cells is not clear. However, shedding trans- in (6). Thus, the process of shedding is an important mecha- forms cell surface receptor syndecans into soluble forms, nism for controlling diverse cellular functions. which, like growth factors, may act as novel ligands to induce Recently, receptor shedding has been identified as a com- cellular responses by association with other cell surface recep- mon mechanism in various diseases, including cancer and car- tors. It is becoming interestingly evident that shed syndecans diovascular disease. For example, proteolysis of the receptor also contribute significantly to syndecan functions in cancer for advanced glycation end products (RAGE) (7-9) is able to biology. This review presents current knowledge about synde- suppress the development of Alzheimer's disease; therefore, can shedding and its functional significance, particularly in the the modulation of RAGE proteolysis is considered a potential context of cancer. [BMB reports 2010; 43(5): 305-310] novel therapeutic target for the treatment of Alzheimer's disease (9, 10). Stimulation of platelet 5-hydroxytryptamine (5-HT) receptors (5-HT2ARs) by circulating serotonin (5-HT) induces INTRODUCTION TACE-mediated shedding of GPIbα, which is capable of modulating cardiovascular disease (11). A high level of the P-cadher- Shedding is defined as ”releasing and/or separating some- in soluble fragment, which is possibly released via extracellular thing”. The phenomenon of shedding can be found in bio- domain shedding, has been correlated with an increased risk logical systems, exemplified by viral shedding and receptor for breast cancer (12). A soluble fragment of the Type III TGF-β shedding. Viral shedding is the process of expelling virus par- receptor generated by ectodomain shedding has been shown ticles from the body, whereas receptor shedding is the process to suppress the invasion of non-small cell lung cancer (13), whereby the extracellular domain of transmembrane proteins and the progression of pancreatic cancer (14). In addition, the is cleaved (separated) and released from the cell surface. shed soluble domain of the endothelial-specific Tie2 receptor Receptor shedding has been implicated in a number of com- might be a prognostic indicator in patients with acute myeloid mon regulatory mechanisms. For example, epidermal growth leukemia (15); and serum soluble interleukin 2 receptor might factor receptor (EGFR) ligands are synthesized as transmem- act as a new biochemical marker of neoplasm activity in adults brane proteins, and shedding of the extracellular domain and children (16). On the other hand, tissue inhibitor metal- loproteinases-3 (TIMP-3), which inhibits the shedding of *Corresponding author. Tel: 82-2-3277-3761; Fax: 82-2-3277-3760, TNF-α receptors, Fas, and p55TNF receptor 1, might facilitate E-mail: [email protected] apoptosis of cancer cells. Although is uncertain whether shedding is a direct cause of cancer, it is clear that shedding is an Received 29 March 2010 important regulatory mechanism in carcinogenesis. Keywords: Cancer, Matrix metalloproteinase (MMP), Shedding, Syn- decan http://bmbreports.org BMB reports 305 Syndecan shedding in cancer Sojoong Choi, et al.

Syndecans and cancer Syndecan shedding enzymes

Syndecans, a family of cell surface heparansulfate proteogly- Since syndecan shedding involves releases of the extracellular cans, are known to play critical roles in cancer cell biology. domain, it would most likely be mediated by extracellular The biological functions of syndecans as cell surface receptors proteases. Several matrix metalloproteases (MMPs), zinc-de- have been well summarized in several excellent reviews pendent endopetidases that play an important role at different (17-19). Each syndecan appears to have different role in the stages of cancer progression, have been reported to regulate regulation of cancer-related processes. Syndecan-1 plays an the shedding of syndecans. MMP-9 has been implicated in the important role in the growth, survival, vasculogenesis, and stromal cell-derived factor-1 (SDF-1)-induced shedding of syn- metastasis of various cancers, including myelomas (20) and decan-1 and syndecan-4 in HeLa cervical cancer cells (31). In breast (21), bladder (22), ovary (23), prostate (24) and colon these cells, siRNA-mediated knockdown of MMP-9 reduced cancers (25). For instance, knockdown of syndecan-1 using shedding of syndecan-1 and syndecan-4, despite the continued small interfering RNAs (shRNA) promotes apoptosis of myelo- presence of SDF-1, confirming that MMP-9 mediates shedding ma cells and dramatically diminishes tumor cell growth (20). of syndecan-1 and syndecan-4. There is also evidence for the Knockdown of syndecan-1 also decreases vascular endothelial involvement of other MMPs. For example, Chen et al showed growth factor-A (VEGF-A) levels and vasculogenesis in mouse that epithelial injury induced syndecan-1 shedding from the models (20). Consistent with this, overexpression of synde- epithelium of wild-type mice but not from the epithelium of can-1 has bee shown to induce approximately a twofold in- MMP-7 knockout mice (32); and Endo et al showed that mem- crease in the proliferation of endometrial cancer cells (26). brane type matrix metalloproteinase-1 (MT1-MMP) promoted Syndecan-1 mRNA levels are up-regulated in pancreatic can- syndecan-1 shedding through the preferential cleavage of syn- cer in association with accelerated tumor growth, as de- decan-1 core protein Gly245-Leu246 peptide bond. Indeed termined by in situ hybridization and immunohistochemistry syndecan-1 contains a general consensus sequence for cleav- (27). age by MMP-7, MMP-9 and MT1-MMP (33). The shedding of In contrast to syndecan-1, which has been implicated in a syndecan-3 has also been reported in Schwann cells obtained variety of cancer types, the role of syndecan-2 seems to be lim- from the sciatic nerves of 2-4 day-old rats (34). This shedding ited to melanomas and colon and prostate cancers. Syndecan- is reduced in cells treated with the MMP inhibitor Batimastat 2 is dramatically overexpressed in melanomas and several co- (BB-94) (34), providing evidence for the involvement of MMPs lon carcinoma cell types, and up-regulation of syndecan-2 is in mediating syndecan-3 shedding. believed to increase the tumorigenic activity of these cells. ADAMTS1, a member of the disintegrin-like and metal- Moreover, colon cancer cells cultured on syndecan-2 ectodo- loprotease with thrombospondin type-1 motifs family is also main or syndecan-2 antibody show increased adhesion and known to cleave the syndecan-4 ectodomain. After co-trans- spreading (28). Syndecan-2 is also overexpressed in about fecting 293T cells with ADAMTS1 and an N-terminally HA- 90% of prostate cancer patients, and the increased syndecan-2 tagged full-length syndecan-4 construct, a soluble fragment expression enhances the growth of prostate tumor cells (29). In (approximately 6-7 kDa) of HA-tagged syndecan-4 extracellular contrast to other syndecans, which generally function as tumor domain was detected in conditioned media (35). This shed- promoters, syndecan-4 apparently functions as a tumor su- ding of syndecan-4 was reduced by BB-94, a metalloprotease ppressor. Syndecan-4 promotes focal adhesion formation, re- inhibitor that partially inhibits the protease activity of sulting in increased cell adhesion but decreased cell migration, ADAMTS1 (35). Moreover, shedding of both syndecan-1 and effects that collectively reduce cancer cell activity (30). Those -4 was blocked by the peptide hydroxamates BB-2116 and reports have all shown that syndecans play a critical role as BB-1101 (36), which are compounds that were originally de- cell surface receptors in cancer cells. Interestingly, the pres- signed to inhibit zinc-dependent MMPs. ence of a dibasic peptide sequence adjacent to the plasma ADAM17, a disintegrin and metalloproteinase family mem- membrane in all syndecans predicted that the extracellular do- bers, is also known to cleave syndecans. Production of soluble main of syndecan could be cleaved by extracellular proteases. syndecan-1 and -4 was reduced in both ECV304 bladder carci- This has since been experimentally demonstrated and recent noma epithelial cells and A549 lung carcinoma epithelial cells evidence points to shedding of the extracellular domain as a by treatment with GW280264, an inhibitor of ADAM17 and prominent aspect of the function of syndecans. Considered in ADAM10, but not by the ADAM10 inhibitor GI254023 (37). light of the function of syndecans as cell surface receptors, syn- Similarly, the shedding of syndecan-1 and syndecan-4 is stimu- decan shedding seemingly poses a dilemma. However, synde- lated by the recombinant ADAM17 catalytic domain (37). In can shedding might constitute an additional level for control- addition, siRNA-mediated knockdown of ADAM17 reduced ling the function of syndecans, providing a means to attenuate shedding of syndecan-1 and syndecan-4 in ECV304 cells and and/or regulate the amplitude and/or duration of syndecan signals A549 cells (37). ADAM17 activation also mediates release of by modulating the activity of syndecans as cell surface receptors. soluble syndecan-1 and -4 into the bronchoalveolar fluid of

306 BMB reports http://bmbreports.org Syndecan shedding in cancer Sojoong Choi, et al.

mice, as evidenced by the fact that both constitutive and in- giogenic and metastatic potential of tumor cells (47). In myelo- duced syndecan shedding could be prevented by inhibiting ma cells, syndecan-1 shedding is promoted by expression of ADAM17 (37). The pseudomonas virulence factor LasA, an heparanase-1 (48) and by treatment with recombinant hepar- M23 metallopeptidase related to autolytic glycylglycine endo- anase (48). In addition, serum levels of shed syndecan1 are peptidases, is known for stimulating ectodomain shedding of elevated in animals bearing tumors derived from hepar- syndecan-1 (38, 39). Collectively, these observations establish anase-transfected CAG cells (48). Clearly, MMPs are not the that shedding of syndecans is mediated by a number of factors, only mediators of syndecan shedding; several other factors act including MMP-9, MMP-7, MT1-MMP, ADMTS1, ADAM17, cooperatively to regulate syndecan shedding. and LasA. The function of shed syndecans in cancer Regulation of syndecan shedding The cleaved extracellular domain of syndecan plays a role in Syndecan shedding is regulated by several factors, one of multiple pathologies. The most important and well-studied which is growth factors. Subramanian et al. showed that EGF function of shed syndecans are their role(s) in tumorigenesis. increased the shedding of syndecan-1 and syndecan-4 in a MT1-MMP promotes syndecan-1 shedding, and shed synde- concentration-dependent manner, and demonstrated that other can-1 stimulates HEK293T cell migration (33), T47D breast EGF family members, such as EGF, HB-EGF, TGF-α and am- carcinoma cell proliferation (49), and breast carcinoma cell phiregulin, produce the same effects (40). Ding et al showed growth in three-dimensional co-culture (33). Overexpression that FGF-2 enhances the shedding of syndecan-1 in PANC-1 of shed syndecan-1 also promotes an invasive phenotype in pancreatic carcinoma cells (41). Interestingly, it is known that MCF-7 breast cancer cells (50). Heparanase-mediated synde- MMP7 (matrilysin) is frequently overexpressed by pancreatic can-1 shedding within the tumor microenvironment appears to cancer cells (42), and fibroblast growth factor (FGF)-2 induces be associated with an aggressive tumor phenotype. Serum lev- expression and activation of MMP7 together with syndecan-1 els of soluble syndecan-1 are much higher in animals with tu- shedding (41). Increased levels of serum syndecan-1 have mors formed from heparanase-transfected cells, and these ani- been observed in patients with type 2 diabetes treated with in- mals have a significantly higher tumor burden than animals sulin (43). The fact that this association represents a causal bearing tumors from control-transfected cells (51). Heparanase linkage is supported by the observation that exogenous insulin up-regulation stimulates enhanced ERK signaling, which acts promotes time-dependent shedding of syndecan-1 into the se- through upregulation of MMP-9 and uPA/uPAR to enhance rum (43). In 3T3-L1 adipocytes, insulin has been shown to in- syndecan-1 shedding. Such shed syndecan-1 stimulates a dra- duce a dose- and time-dependent shedding of syndecan-1 and matic increase in the aggressive behavior of myeloma tumors syndecan-4 that is also metalloproteinase-dependent (44). (51). Treatment of human umbilical vein endothelial cells with Growth factors are also involved in the regulation of synde- conditioned media from heparanase-transfected myeloma cells can-2 shedding. Fears et al reported that treatment of micro- significantly stimulates syndecan-1 shedding and VEGF ex- vascular endothelial cells with EGF, FGF-2, or VEGF induced pression. Heparansulfate chains of shed syndecan-1 mediate shedding of syndecan-2 (17). interaction with VEGF, resulting in formation of a syndecan-1/ Syndecan shedding is also affected by other factors, includ- VEGF complex that activates integrin and VEGF receptors, and ing inflammatory cytokines, bacterial toxins, oxidative stress thereby stimulates endothelial invasion (48). Similar to shed and others. For example, chronic inflammation promotes shed- syndecan-1, the extracellular domains of syndecan-2 and syn- ding of syndecan-1 into serum (41); Staphylococcus aureus be- decan-4 are also known to increase endothelial cell-mediated ta-toxin stimulates ectodomain shedding of syndecan-1, which angiogenesis. Recombinant syndecan-2 ectodomain promotes induces neutrophil-mediated lung injury; and oxidative stress membrane capillary tube formation in mouse brain micro- induces syndecan-1 shedding, which causes neutrophil che- vascular endothelial cells (44), and the ectodomain of synde- motaxis and abnormal wound healing (45). Phorbol 12- myr- can-4 cleaved by secreted ADAMTS1 causes altered dis- istate 13-acetate (PMA), an activator of protein kinase C (PKC), tribution of cytoskeleton components, functional loss of adhe- also enhances shedding of syndecan-1 from the surface of hu- sion, gain of migratory capacity, and angiogenesis (35). man myeloma cells (46). The effects of PMA on syndecan-1 Anti-tumorigenic effects of shed syndecans have also been shedding presumably involve PKC-dependent activation of the reported. The membrane-bound syndecan-1 promotes pro- appropriate protease, but the pathway has yet been establi- liferation of MCF-7 breast cancer cells; overexpression of con- shed. Interestingly, the cell surface heparansulfate chains of stitutively shed syndecan-1 inhibits MCF-7 proliferation (50). syndecans greatly affect syndecan shedding. The expression of In addition, shed syndecan-1 inhibits alveolar epithelial wound heparanase-1, an endoglycosidase that degrades heparansul- healing and promotes fibrogenesis (45), and decreases in- fate chains in the extracellular matrix and cell surface, is rare vasion of TIMP-1-sensitive breast cancer cell invasion (50). in normal tissues. However, heparanase-1 is up-regulated in Moreover, treatment of human endothelial cells with synde- many human tumors in association with an increase in the an- can-1 ectodomain decreases vitronectin attachment and angio- http://bmbreports.org BMB reports 307 Syndecan shedding in cancer Sojoong Choi, et al.

genesis (52). Although there are controversies surrounding the plasminogen activator (uPA) receptor and E-cadherin (50). various proposed roles of shed syndecans in cancer, it is clear These studies imply that shed syndecans might act as ligands that shed syndecans serve multiple functions, and may differ- to induce gene expression. entially and variably affect various cellular behaviors. CONCLUSION Molecular mechanisms of shed syndecan-mediated carcinogenesis In this review, we have focused on the function of shed syndecans in carcinogenesis. Though carcinogenesis is clearly one Shedding produces a soluble form of syndecan in the ex- context in which shedding of syndecans is enhanced, it should tracellular environment, and multiple lines of evidence suggest be noted that regulation of syndecan shedding may be equally that shed syndecans are responsible for enhancing the activity important in other, as yet undefined, settings. Moreover, the of cancer cells. While the exact molecular mechanism(s) by importance of syndecan’s function as adhesion receptors should which shed syndecans mediate tumorigenic activity in cancer not be underestimated. Each syndecan has its own role(s) in cells remain unknown, the following four-point model de- different aspects of cancer progression, but all are important scribes a reasonable scenario. regulators of human carcinogenesis in their capacity as cell First, shedding causes release of syndecan-bound signaling surface receptors. However, the phenomenon of extracellular protein(s) to generate a new signal or modify an existing domain shedding adds a puzzling wrinkle to the effort to char- signal. Based on the promiscuous binding behavior of synde- acterize the functions of syndecans. Is the importance of cell cans, it is possible that the extracellular domain of syndecan surface syndecans in controlling cancer cell activities related might bind to a variety of proteins and growth factors, some of to their receptor functions, or is the shed extracellular domain which may regulate tumor growth (i.e. TGF-β). If shedding of syndecans, acting as a ligand, the major player? In all like- were to release syndecan-bound growth-inhibiting factors from lihood, syndecans function as receptors as well as ligands in normal cells, this would cause these confined factors to be re- certain circumstances. Extracellular-domain shedding causes leased from the cell surface leading to disinhibition of cell transformation of cell surface receptor syndecans into soluble proliferation. In this case, syndecan shedding would attenuate ligand-like growth factors. Therefore, extracellular-domain shed- the function of the syndecan as a cell surface receptor, but en- ding allows syndecans to contribute to carcinogenesis in many hance its caner-promoting activity. ways, and represents a new paradigm of syndecan functions in Second, shed syndecan may not only release signaling pro- cancer. It is not clear yet whether syndecan shedding is di- teins, but also enhance their activity. Because syndecan pro- rectly involved in causing cancer, or whether the extracellular teins contain heparansulfate chains, they may be capable of domain of shed syndecans plays positive or negative roles in binding and regulating secreted signaling molecules, such as carcinogenesis. However, what is clear is that further inves- transforming growth factor and fibroblast growth factors, tigations to establish the detailed mechanism(s) underlying the which promote proliferation of cancer cells. In addition, and process of syndecan shedding and precisely define the func- perhaps more significantly, syndecan-2 may also regulate the tions of syndecans are necessary if we are to understand how activity of secreted proteins. It is quite possible that shed syn- syndecans control carcinogenesis and develop novel synde- decan-2-bound FGF-2 more efficiently interacts with FGF re- can-targeted cancer therapies. ceptor than FGF alone. As a result, syndecan-2 may enhance angiogenesis via FGF receptor signaling (53). Acknowledgements Third, shed syndecans may eliminate inhibitory soluble This study was supported by a grant of the Korea Healthcare factors. Syndecan-1 shedding facilitates the resolution of neu- technology R&D Projects, Ministry for Health, Welfare, and trophilic inflammation by removing sequestered CXC chemo- Family Affairs, Republic of Korea (A090165 to ESO) and in kines. Consistent with this, treatment with a shedding inhibitor part by grant No. R15-2006-020 from the NCRC program of prevents the clearance of CXC chemokines and exacerbates the MEST and the KOSEF through the Center for Cell Signaling disease (54). Therefore, shed syndecans may promote cancer & Drug Discovery Research at Ewha Womans University. by sequestrating inhibitory signals. Fourth, shed syndecans could function as new soluble REFERENCES ligands. Because shed syndecan-2 expression is highly increased in colon cancer cells, these cells could presumably 1. Gee, J. M. and Knowlden, J. M. (2003) ADAM metal- produce large amounts of soluble ectodomain polypeptide, loproteases and EGFR signalling. Breast Cancer Res. 5, which could bind to (unknown) carcinogenic receptors. These 223-224. 2. Lee, D. C., Sunnarborg, S. W., Hinkle, C. L., Myers, T. J., events could be dependent on or independent of glyco- Stevenson, M. Y., Russell, W. E., Castner, B. 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